Aggregation of the high-affinity Fc receptors for immunoglobulin E (IgE) (Fc.epsilon.RI) on the surface of mast cells initiates intracellular signal transduction pathways, involving the tyrosine phosphorylation of cellular proteins, activation of phospholipase C.gamma., hydrolysis of phosphoinositide, increase in intracellular calcium, activation of protein kinase C and the stimulation of phosphatidylinositol 3-kinase. These signal transduction pathways are believed to be involved in the exocytic release of inflammatory mediators such as vasoactive amines, cytokines, and lipid metabolites. The production of cytokines by mast cells is a critical event that influences the pathogenesis of allergic inflammation in asthma and other allergic disorders.
In addition to the activation of phospholipase C.gamma. and protein kinase C, which appears to be essential for the Fc.epsilon.RI-mediated release of preformed mediators, the aggregation of Fc.epsilon.RI on rat basophilic leukemia 2H3 (RBL-2H3) cells has been shown to induce histamine and leukotriene release. Except for the activation of the extracellular signal-regulated kinases/mitogen activated protein kinases (ERKs/MAPKs), however, the downstream consequences of early activation events in a signal transduction pathway leading to cytokine production are not well defined.
The extracellular signal-regulated kinases (ERKs), ERK1 and ERK2, are serine/threonine protein kinases that are activated through concomitant phosphorylation of tyrosine and threonine residues. Prior to the current invention, it was thought that ERKs were one of the intermediates in the signal transduction pathway leading to increases in gene transcription and proliferation, including cytokine gene transcription. ERKs phosphorylate specific transcription factors including members of the Ets family, such as Elk-1, and it has been reported that ERKs are activated via Fc.epsilon.RI on mast cells.
Despite the current understanding of early signal transduction events in hematopoietic cells, there remains a need to elucidate signal transduction pathways that specifically regulate cytokine production in such cells and to determine what molecules and/or functional elements of such molecules are responsible for regulating such cellular pathways. There is also a need for products and processes that permit the effective regulation of specific steps in such a signal transduction pathway. Regulation of specific steps of a signal transduction pathway which regulate cytokine production permits the implementation of predictable controls of such signal transduction in cells, thereby allowing modulation of the effects of cytokine production in diseases wherein such modulation can ameliorate disease pathogenesis.